The invention relates to new vitamin D derivatives of general formula I 
process for their production, intermediate products of the process as well as the use for the production of pharmaceutical agents.
Natural vitamins D2 and D3 are inherently biologically inactive and are converted into biologically active metabolites [1xcex1,25-dihydroxy vitamin D3 (calcitriol) or -D2] only after hydroxylation at C-atom 25 in the liver and at C-atom 1 in the kidney. The action of the active metabolites involves the regulation of the calcium and phosphate concentration in the serum; they counteract a dropping of the calcium concentration in the serum by increasing the calcium absorption in the intestine and under certain circumstances promoting calcium mobilization from the bones. FIG. 1 shows the structure of some known vitamin D derivatives.
In addition to their pronounced effect on the calcium and phosphate metabolism, the active metabolites of vitamins D2 and D3 and their synthetic derivatives have a proliferation-inhibiting and differentiation-stimulating action on tumor cells and normal cells, such as, for example, skin cells. In addition, a pronounced effect on cells of the immune system (inhibiting of proliferation and interleukin 2-synthesis of lymphocytes, increase of cytotoxicity and phagocytosis in vitro of monocytes) has been found, which manifests itself in an immunomodulatory action, and finally, because of a stimulating action on bone-forming cells, an increased formation of bone in normal and osteoporotic rats is found [R. Bouillon et al. xe2x80x9cShort Term Course of 1,25-(OH)2D3 Stimulates Osteoblasts But Not Osteoclasts,xe2x80x9d Calc. Tissue Int. 49, 168 (1991)].
All actions are mediated by bonding to the vitamin D receptor. Because of the bonding, the activity of specific genes is regulated.
When biologically active metabolites of vitamins D2 and D3 are used, a toxic effect on the calcium metabolism is produced (hypercalcemia).
By structural manipulations of the side chain, therapeutically usable effectiveness can be separated from undesirable hypercalcemic activity. A suitable structural variant is the introduction of a 24-hydroxy group.
1xcex1-Cholecalciferols that are hydroxylated in 24-position are already described in DE 25 26 981. They have a lower toxicity than the corresponding non-hydroxylated 1xcex1-cholecalciferol. Further, 24-hydroxy derivatives are described in the following patent applications: DE 39 33 034, DE 40 03 854, DE 40 34 730, EP 0 421 561, EP 0 441 467, WO 87/00834, and WO 91/12238.
Finally, 25-carboxylic acid derivatives of calcitriol that are hydroxylated at C-24 are described in WO 94/07853, and said derivatives exhibit a more advantageous spectrum of action than calcitriol. The equivalent is also true for new vitamin D derivatives with other substituents at C-25 (WO 97/00242). While the ability to trigger a hypercalcemia is considerably weakened, proliferation-inhibiting and differentiation-stimulating actions are maintained. Generally, however, the introduction of the 24-hydroxyl group results in metabolic destabilization of the derivatives, especially if a cyclopropyl ring is in the neighboring position. For this reason, these compounds are only conditionally suitable for systemic administration.
There is therefore a need for new vitamin D derivatives that have as advantageous or improved a spectrum of action as the compounds that are described in the prior art (especially WO 94/07853 and WO 97/00242), but that are better suited for systemic administration owing to their higher metabolic stability.
The object of this patent application is therefore to make available such vitamin D derivatives. This object is achieved by the compounds that are disclosed in the claims.
This invention therefore relates to vitamin D derivatives of general formula I, 
in which
Y1 means a hydrogen atom, a hydroxyl group, a fluorine, chlorine or bromine atom or a group xe2x80x94O(CO)R5, in which
R5 is an aliphatic or aromatic radical with 1 to 12 C atoms,
Y2 means a hydrogen atom or a group xe2x80x94(CO)R6, in which
R6 is an aliphatic or aromatic radical with 1 to 12 C atoms,
and group Y2O can be present both in naturally occurring situation (3xcex2) and in epimeric situation (3xcex1),
R1 and R2 each mean a hydrogen atom or together an exocyclic methylene group,
R3 and R4, independently of one another, mean a hydrogen atom, a chlorine or fluorine atom, an alkyl group with 1 to 4 carbon atoms, together a methylene group or together with quaternary carbon atom 20 a 3- to 7-membered, saturated or unsaturated carbocyclic ring,
V and W together mean an E-double bond or V means a hydroxyl group and W means a hydrogen atom, or V and W each mean hydrogen atoms,
X1 and X2, independently of one another, mean a hydrogen atom, a hydroxyl group, a group xe2x80x94OR7 or O(CO)R7, in which
R7 is an aliphatic or aromatic radical with 1 to 12 C atoms,
xe2x80x83or a group PO(OR8)2, a group PO(N(R8)2)2 or a group PO(R8)2, a group OPO(OR8)2, a group OPO(N(R8)2)2 or a group OPO(R8)2 or a group CH2xe2x80x94PO(OR8)2, a group CH2xe2x80x94PO(N(R8)2)2 or a group CH2xe2x80x94PO(R8)2, in which
R8, independently of one another, are a hydrogen atom or an aliphatic or aromatic radical with 1 to 12 C atoms,
xe2x80x83or
X1 and X2 together stand for a carbonyl group,
p means the number 1 or 0,
E1 means a group PO(OR9)2, a group PO(N(R9)2)2, a group PO(R9)2 or a group CO2R9 in which
R9, independently of one another, are a hydrogen atom or an aliphatic or aromatic radical with 1 to 12 C atoms,
E2 means a group PO(OR9)2, a group PO(N(R9)2)2, a group PO(R9)2, a halogen atom (fluorine, chlorine, bromine), an aliphatic or aromatic radical with 1 to 12 C atoms or a hydrogen atom,
Q means a hydrogen atom, an aliphatic or aromatic radical with 1 to 12 C atoms, a hydroxyl group, a group xe2x80x94O(CO)R10, a fluorine, chlorine or bromine atom, an amino group or an NHR10 or N(R10)2 group, in which
R10 is an aliphatic or aromatic radical with 1 to 12 C atoms,
xe2x80x83or
X1 and E2 together mean a double bond and at the same time X2 means a hydrogen atom or a group Oxe2x80x94Z, in which
Z means an aliphatic or aromatic radical with 1 to 12 C atoms, an aliphatic or aromatic acyl group with 1 to 12 C atoms or a group E2,
xe2x80x83or
X1, X2, E2 and Q together mean a triple bond.
The invention also relates to a process for the production of the compounds according to the invention, intermediate products of the production process as well as the use of the compounds according to the invention for the production of pharmaceutical agents.
Especially advantageous embodiments of the invention are the subject of the subclaims.
Groups E1 and E2, i.a., stand for phosphonic acid derivatives or carboxylic acid derivatives or for phosphine oxide derivatives. The term phosphonic acid derivatives or carboxylic acid derivatives comprises the free phosphonic acids or carboxylic acids (xe2x80x94PO3H2, xe2x80x94CO2H), phosphonic- or carboxylic acid esters (xe2x80x94PO3(R9)2, xe2x80x94CO2R9), phosphonic- or carboxylic acid amides (e. g., xe2x80x94PO(N(R9)2)2, xe2x80x94CO(NR9)2, xe2x80x94PO(NHR9)2, xe2x80x94CO2NHR9), but also phosphonic acid monoesters or -amides, such as, e.g., PO(OH)OR9, PO(OH)N(R9)2.
Groups X1 and X2, i.a., stand for hydrogen atoms, hydroxyl groups, etherified or esterified hydroxyl groups. They can also stand for (E1 and E2) already defined above under phosphoric acid derivatives (xe2x80x94PO3H2, xe2x80x94PO3(R8)2, xe2x80x94PO(N(R8)2)2, xe2x80x94PO(NHR8)2, but also phosphonic acid monoesters or amides). This conformation and its synthesis is described in, for example, Example 29. Groups X1 and X2 together can also stand for a carbonyl group, however (see, e.g., Example 10).
It is common in all compounds according to the invention that at least one phosphorus-containing group is contained that is bonded to the vitamin D skeleton by a phosphorus-carbon bonding. Especially preferred are compounds in which both groups (E1 and E2) stand for phosphonic acid derivatives.
Index p stands for numbers 1 or 0. If p stands for 0, this means that C atom 25 does not exist, and group E1 is bonded directly to C-24. This conformation and its synthesis is described by way of example in Examples 29 and 30.
Groups R3 and R4, independently of one another, can mean a hydrogen atom, a chlorine or fluorine atom, an alkyl group with 1 to 4 carbon atoms (methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl), together a methylene group or together with quaternary carbon atom 20 a 3- to 7-membered saturated or unsaturated carbocyclic ring.
For R3 and R4, the following preferred combinations apply: R3=H, R4=methyl or R3=methyl, R4=H; R3=F, R4=methyl or R3=methyl, R4=F; R3, R4=methyl; R3 and R4 together form a methylene group or together with quaternary carbon atom 20 form a cyclopropyl ring.
Optional radicals R5, R6, R7, R8, R9 and R10 are organic groups with 1 to 12 C atoms. These radicals can be saturated or unsaturated, branched or unbranched, acyclic, carbocyclic or heterocyclic. Examples of radicals R5, R6, R7, R8, R9 and R10 are methyl, ethyl, propyl, i-propyl, butyl or phenyl groups. The radicals of naturally occurring amino acids, such as, e.g., xe2x80x94CH2xe2x80x94CH(CH3)2, xe2x80x94CH2xe2x80x94Ph, xe2x80x94CH2OH, xe2x80x94CH(OH)xe2x80x94CH3, xe2x80x94CH2SH, xe2x80x94CH2xe2x80x94SCH3, xe2x80x94CH2CO2H, xe2x80x94CH2CH2xe2x80x94CO2H, xe2x80x94(CH2)4xe2x80x94NH2, xe2x80x94(CH2)3xe2x80x94C(NH)NH2, but also the radicals of the amino acids tryptophan, tyrosine or histamine, are also possible, however.
Preferred radicals R5, R6, R7, R8, R9 and R10 are derived from C1 to C9 alkanecarboxylic acids, especially C2 to C5 alkanecarboxylic acids, such as, for example, acetic acid, propionic acid, butyric acid or pivaloyl acid. Among the aromatic groups, the phenyl group and substituted phenyl groups are preferred.
Preferred radicals for Y are Y1=a hydroxyl group or xe2x80x94O(CO)R5 and Y2=a hydrogen atom or xe2x80x94(CO)R6. Y1=a hydroxyl group and Y2=a hydrogen atom are especially preferred.
Groups V and W are respectively hydrogen atoms or either together form an E-double bond or V is a hydroxyl group and W is a hydrogen atom. The possibilities for the structural element in question are pictured below: 
Within the scope of this invention, the following conformation is especially significant: V and W and X1 and E2 in each case mean an E-double bond, while X2 and Q are hydrogen atoms. This conformation and its synthesis is described in, for example, Example 27.
In addition, the conformation is significant that V and W together form an E-double bond, X1 and E2 form an E- or Z-double bond, X2 is a group xe2x80x94OZ, and Q means a hydrogen atom.
In addition, the conformation that X1, X2, E2 and Q together form a triple bond is significant. This conformation and its synthesis is described in, for example, Examples 16 and 17.
Finally, the conformation that E2 and Q are halogen atoms (especially chlorine and fluorine) is of special importance within the scope of this invention. This conformation and its synthesis is described in, for example, Examples 18, 19 and 20.
Of the compounds of general formula I according to the invention, the following compounds are quite especially preferred:
I. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester
II. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester
III. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester
IV. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester
V. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester
VI. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester
VII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid bis(1-methylethyl)ester
VIII. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid bis(1-methylethyl)ester
IX. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid bis(1-methylethyl)ester
X. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipropyl ester
XI. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipropyl ester
XII. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipropyl ester
XIII. (5Z,7E,22E)-(1S,3R)-1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dibutyl ester
XIV. (5Z,7E,22E)-(1S,3R24S)-1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dibutyl ester
XV. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dibutyl ester
XVI. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipentyl ester
XVII. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipentyl ester
XVIII. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipentyl ester
XIX. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diphenyl ester
XX. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diphenyl ester
XXI. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diphenyl ester
XXII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24a,24a-diyl)bis[phosphonic acid dimethyl ester]
XXIII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24a,24a-diyl)bis[phosphonic acid diethyl ester]
XXIV. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24a,24a-diyl)bis[phosphonic acid dipropyl ester]
XXV. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24a,24a-diyl)bis[phosphonic acid dibutyl ester]
XXVI. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24a,24a-diyl)bis[phosphonic acid bis(1-methylethyl)ester]
XXVII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24a,24a-diyl)bis[phosphonic acid diphenyl ester]
XXVIII. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid dimethyl ester
XXIX. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid diethyl ester
XXX. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid dipropyl ester
XXXI. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid dibutyl ester
XXXII. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid bis(1-methylethyl)ester
XXXIII. (5Z,7E,22E)-(1S,3R)-24-(Diphenylphosphinyl)-9,10-secochola-5,7,10(19),22-tetraene-1,3-diol
XXXIV. (5Z,7E,22E)-(1S,3R)-24-(Dimethylphosphinyl)-9,10-secochola-5,7,10(19),22-tetraene-1,3-diol
XXXV. (5Z,7E,22E)-(1S,3R)-24-(Diethylphosphinyl)-9,10-secochola-5,7,10(19),22-tetraene-1,3-diol
XXXVI. (5Z,7E,22E)-(1S,3R)-24-(Dipropylphosphinyl)-9,10-secochola-5,7,10(19),22-tetraene-1,3-diol
XXXVII. (5Z,7E,22E)-(1S,3R)-24-(Dibutylphosphinyl)-9,10-secochola-5,7,10(19),22-tetraene-1,3-diol
XXXVIII. (5Z,7E,22E,24E)-(1S,3R)-Phosphoric acid[1,3-Dihydroxy-24a-(dimethoxy)phosphinyl-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24-yl]dimethyl ester
XXXIX. (5Z,7E,22E,24Z)-(1S,3R)-Phosphoric acid[1,3-dihydroxy-24a-(dimethoxy)phosphinyl-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24-yl]dimethyl ester
XL. (5Z,7E,22E,24E)-(1S,3R)-Phosphoric acid[24a-(diethoxy)phosphinyl-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24-yl]diethyl ester
XLI. (5Z,7E,22E,24Z)-(1S,3R)-Phosphoric acid[24a-(diethoxy)phosphinyl-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24-yl]diethyl ester
XLII. (5Z,7E,22E,24E)-(1S,3R)-Phosphoric acid[1,3-dihydroxy-24a-(dipropoxy)phosphinyl-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24-yl]dipropyl ester
XLIII. (5Z,7E,22E,24Z)-(1S,3R)-Phosphoric acid[1,3-dihydroxy-24a-(dipropoxy)phosphinyl-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24-yl]dipropyl ester
XLIV. (5Z,7E,22E,24E)-(1S,3R)-Phosphoric acid[24a-(dibutoxy)phosphinyl-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24-yl]dibutyl ester
XLV. (5Z,7E,22E,24Z)-(1S,3R)-Phosphoric acid[24a-(dibutoxy)phosphinyl-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24-yl]dibutyl ester
XLVI. (5Z,7E,22E,24E)-(1S,3R)-Phosphoric acid[24a-[bis(1-methylethoxy)phosphinyl]-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24-yl]bis(1-methylethyl) ester
XLVII. (5Z,7E,22E,24Z)-(1S,3R)-Phosphoric acid[24a-[bis(1-methylethoxy)phosphinyl]-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24-yl]bis(1-methylethyl)ester
XLVIII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-monomethyl ester
XLIX. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9, 10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-monoethyl ester
L. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-mono(1-methylethyl)ester
LI. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-monopropyl ester
LII. (5Z,7E,22E)-(1S,3R)-1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-monobutyl ester
LIII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid
LIV. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid-monomethyl ester
LV. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid-monoethyl ester
LVI. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid-mono(1-methylethyl)ester
LVII. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid-monopropyl ester
LVIII. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid-monobutyl ester
LIX. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid
LX. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24,24a-diyl)bis[phosphonic acid dimethyl ester]
LXI. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24,24a-diyl)bis[phosphonic acid diethyl ester]
LXII. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24,24a-diyl)bis[phosphonic acid-bis(1-methylethyl)ester]
LXIII. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24,24a-diyl)bis[phosphonic acid dipropyl ester]
LXIV. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24,24a-diyl)bis[phosphonic acid dibutyl ester]
LXV. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-nor-9,10-secocholesta-5,7,10(19),22-tetraene-26,27-diyl)bis[phosphonic acid dimethyl ester]
LXVI. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-nor-9,10-secocholesta-5,7,10(19),22-tetraene-26,27-diyl)bis[phosphonic acid diethyl ester]
LXVII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-nor-9,10-secocholesta-5,7,10(19),22-tetraene-26,27-diyl)bis[phosphonic acid-bis(1-methylethyl)ester]
LXVIII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-nor-9,10-secocholesta-5,7,10(19),22-tetraene-26,27-diyl)bis[phosphonic acid dipropyl ester]
LXIX. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-nor-9,10-secocholesta-5,7,10(19),22-tetraene-26,27-diyl]bis[phosphonic acid dibutyl ester]
LXX. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-nor-9,10-secocholesta-5,7,10(19),22-tetraene-26,27-diyl)bis[phosphonic acid]
LXXI. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaene-24a,24a-diyl)bis[phosphonic acid dimethyl ester]
LXXII. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaene-24a,24a-diyl)bis[phosphonic acid diethyl ester]
LXXIII. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaene-24a,24a-diyl)bis[phosphonic acid-bis(1-methylethyl)ester]
LXXIV. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaene-24a,24a-diyl)bis[phosphonic acid dipropyl ester]
LXXV. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaene-24a,24a-diyl)bis[phosphonic acid dibutyl ester]
LXXVI. (5Z,7E,22E,24E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaene-24a,24a-diyl)bis[phosphonic acid]
LXXVII. (5Z,7E,22E,24Z)-(1S,3R)-(24a-Chloro-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid dimethyl ester
LXXVIII. (5Z,7E,22E,24Z)-(1S,3R)-(24a-Chloro-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid diethyl ester
LXXIX. (5Z,7E,22E,24Z)-(1S,3R)-(24a-Chloro-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid-bis(1-methylethyl)ester
LXXX. (5Z,7E,22E,24Z)-(1S,3R)-(24a-Chloro-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid dipropyl ester
LXXXI. (5Z,7E,22E,24Z)-(1S,3R)-(24a-Chloro-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid dibutyl ester
LXXXII. (5Z,7E,22E,24Z)-(1S,3R)-(24a-Chloro-1,3-dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22,24-pentaen-24a-yl)phosphonic acid
LXXXIII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)phosphonic acid dimethyl ester
LXXXIV. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)phosphonic acid diethyl ester
LXXXV. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)phosphonic acid-bis(1-methylethyl)ester
LXXXVI. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)phosphonic acid dipropyl ester
LXXXVII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)phosphonic acid dibutyl ester
LXXXVIII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)phosphonic acid-monomethyl ester
LXXXIX. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)-phosphonic acid-monoethyl ester
XC. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)phosphonic acid-mono-(1-methylethyl)ester
XCI. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)phosphonic acid-monopropyl ester
XCII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)phosphonic acid-monobutyl ester
XCIII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24-in-24a-yl)phosphonic acid
XCIV. (5Z,7E,22E)-(1S,3R,24S)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester
XCV. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester
XCVI. (5Z,7E,22E)-(1S,3R,24S)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester
XCVII. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester
XCVIII. (5Z,7E,22E)-(1S,3R,24S)-24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-bis(1-methylethyl)ester
XCIX. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-bis(1-methylethyl)ester
C. (5Z,7E,22E)-(1S,3R,24S)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipropyl ester
CI. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipropyl ester
CII. (5Z,7E,22E)-(1S,3R,24S)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dibutyl ester
CIII. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dibutyl ester
CIV. (5Z,7E,22E)-(1S,3R,24S)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid
CV. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Dichloro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid
CVI. (5Z,7E,22E)-(1S,3R,24S)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester
CVII. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester
CVIII. (5Z,7E,22E)-(1S,3R,24S)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester
CIX. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester
CX. (5Z,7E,22E)-(1S,3R,24S)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-bis(1-methylethyl)ester
CXI. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-bis(1-methylethyl)ester
CXII. (5Z,7E,22E)-(1S,3R,24S)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipropyl ester
CXIII. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipropyl ester
CXIV. (5Z,7E,22E)-(1S, 3R,24S)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dibutyl ester
CXV. (5Z,7E,22E)-(1S,3R,24R)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dibutyl ester
CXVI. (5Z,7E,22E)-(1S,3R,24S)-(24a,24a-Difluoro-1,3,24-trihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid
CXVII. (5Z,7E,22E)-(1S,3R)-(24a,24a-Difluoro-1,3-dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester
CXVIII. (5Z,7E,22E)-(1S,3R)-(24a,24a-Difluoro-1,3-dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester
CXIX. (5Z,7E,22E)-(1S,3R)-(24a,24a-Difluoro-1,3-dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-bis(1-methylethyl)ester
CXX. (5Z,7E,22E)-(1S,3R)-(24a,24a-Difluoro-1,3-dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipropyl ester
CXXI. (5Z,7E,22E)-(1S,3R)-(24a,24a-Difluoro-1,3-dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dibutyl ester
CXXII. (5Z,7E,22E)-(1S,3R)-(24a,24a-Dichloro-1,3-dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester
CXXIII. (5Z,7E,22E)-(1S,3R)-(24a,24a-Dichloro-1,3-dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester
CXXIV. (5Z,7E,22E)-(1S,3R)-(24a,24a-Dichloro-1,3-dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-bis(1-methylethyl)ester
CXXV. (5Z,7E,22E)-(1S,3R)-(24a,24a-Dichloro-1,3-dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipropyl ester
CXXVI. (5Z,7E,22E)-(1S,3R)-(24a,24a-Dichloro-1,3-dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dibutyl ester
CXXVII. (5Z,7E,22E)-(1S,3R)-(26,27-Diethenyl-1,3-dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dimethyl ester
CXXVIII. (5Z,7E,22E)-(1S,3R)-(26,27-Diethenyl-1,3-dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid diethyl ester
CXXIX. (5Z,7E,22E)-(1S,3R)-(26,27-Diethenyl-1,3-dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid-bis(1-methylethyl)ester
CXXX. (5Z,7E,22E)-(1S,3R)-(26,27-Diethenyl-1,3-dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid propyl ester
CXXXI. (5Z,7E,22E)-(1S,3R)-(26,27-Diethenyl-1,3-dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid butyl ester
CXXXII. (5Z,7E,22E)-(1S,3R)-(26,27-Diethenyl-1,3-dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid
CXXXIII. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-26-ethenyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dimethyl ester
CXXXIV. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-26-ethenyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid diethyl ester
CXXXV. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-26-ethenyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid-bis(1-methylethyl)ester
CXXXVI. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-26-ethenyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dipropyl ester
CXXXVII. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-26-ethenyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dibutyl ester
CXXXVIII. (5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-26-ethenyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid
CXXXIX. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dimethyl ester
CXL. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid diethyl ester
CXLI. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid-bis(1-methylethyl)ester
CXLII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dipropyl ester
CXLIII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dibutyl ester
CXLIV. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid
CXLV. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-26,27-dimethyl-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dimethyl ester
CXLVI. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-26,27-dimethyl-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid diethyl ester
CXLVII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-26,27-dimethyl-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid-bis(1-methylethyl)ester
CXLVIII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-26,27-dimethyl-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dipropyl ester
CXLIX. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-26,27-dimethyl-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dibutyl ester
CL. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-26,27-dimethyl-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)-phosphonic acid
CLI. (5Z,7E,22E)-(1S,3R,25R)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dimethyl ester
CLII. (5Z,7E,22E)-(1S,3R,25S)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dimethyl ester
CLIII. (5Z,7E,22E)-(1S,3R,25R)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid diethyl ester
CLIV. (5Z,7E,22E)-(1S,3R,25S)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid diethyl ester
CLV. (5Z,7E,22E)-(1S,3R,25R)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19)22-tetraen-25-yl) phosphonic acid-bis (1-methylethyl)ester
CLVI. (5Z,7E,22E)-(1S,3R,25S)-1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid-bis(1-methylethyl)ester
CLVII. (5Z,7E,22E)-(1S,3R,25R)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dipropyl ester
CLVIII. (5Z,7E,22E)-(1S,3R,25S)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dipropyl ester
CLIX. (5Z,7E,22E)-(1S,3R,25R)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dibutyl ester
CLX. (5Z,7E,22E)-(1S,3R,25S)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid dibutyl ester
CLXI. (5Z,7E,22E)-(1S,3R,25R)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid
CLXII. (5Z,7E,22E)-(1S,3R,25S)-(1,3-Dihydroxy-26-methyl-24-oxo-27-nor-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid
CLXIII. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid dimethyl ester
CLXIV. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid dimethyl ester
CLXV. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid diethyl ester
CLXVI. (5Z, 7E ,22 E)-(1S,3R,24R)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid diethyl ester
CLXVII. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid-bis(1-methylethyl)ester
CLXVIII. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid-bis(1-methylethyl)ester
CLXIX. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid dipropyl ester
CLXX. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid dipropyl ester
CLXXI. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid dibutyl ester
CLXXII. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid dibutyl ester
CLXXIII. (5Z,7E,22E)-(1S,3R,24S)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid
CLXXIV. (5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid
CLXXV. (5Z,7E,22E)-(1S,3R)(1,3-Dihydroxy-24-oxo-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid dimethyl ester
CLXXVI. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid diethyl ester
CLXXVII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid-bis(1-methylethyl)ester
CLXXVIII. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid propyl ester
CLXXIX. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid dibutyl ester
CLXXX. (5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid
CLXXXI. (5Z,7E,22E)-(1S,3S)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester
CLXXXII. (5Z,7E,22E)-(1S,3S)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester
CLXXXIII. (5Z,7E,22E)-(1S,3S)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid-bis(1-methylethyl)ester
CLXXXIV. (5Z,7E,22E)-(1S,3S)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dipropyl ester
CLXXXV. (5Z,7E,22E)-(1S,3S)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dibutyl ester
CLXXXVI. (5Z,7E,22E)-(1S,3S)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid.
Of special importance within the scope of this invention are the compounds of general formula Ixe2x80x2 that are mentioned in the priority document (DE 19758119), 
in which
Yxe2x80x21 means a hydrogen atom, a hydroxyl group, a fluorine, chlorine or bromine atom or a group xe2x80x94O(CO)Rxe2x80x25, in which Rxe2x80x25 is an aliphatic or aromatic radical with 1 to 12 C atoms,
Yxe2x80x22 means a hydrogen atom or a group xe2x80x94(CO)Rxe2x80x26, in which Rxe2x80x26 is an aliphatic or aromatic radical with 1 to 12 C atoms,
and group Yxe2x80x22 O can be present both in the naturally occurring situation (3xcex2) and in the epimeric situation (3xcex1),
Rxe2x80x21 and Rxe2x80x22 each mean a hydrogen atom or together an exocyclic methylene group,
Rxe2x80x23 and Rxe2x80x24 independently of one another, mean a hydrogen atom, a chlorine or fluorine atom, an alkyl group with 1 to 4 carbon atoms, together a methylene group or together with quaternary carbon atom 20 a 3- to 7-membered, saturated or unsaturated carbocyclic ring,
Vxe2x80x2 and Wxe2x80x2 together mean an E-double bond or Vxe2x80x2 means a hydroxyl group and Wxe2x80x2 means a hydrogen atom or Vxe2x80x2 and Wxe2x80x2 in each case mean hydrogen atoms,
Xxe2x80x21 and Xxe2x80x22 together mean a carbonyl group or each mean a hydrogen atom or Xxe2x80x22 means a hydrogen atom and Xxe2x80x21 means a hydroxyl group or a group xe2x80x94O(CO)Rxe2x80x27, in which
Rxe2x80x27 is an aliphatic or aromatic radical with 1 to 12 C atoms, or Xxe2x80x21 means a hydrogen atom and Xxe2x80x22 means a hydroxyl group or a group O(CO)Rxe2x80x28, in which
Rxe2x80x28 is an aliphatic or aromatic radical with 1 to 12 C atoms,
xe2x80x83or
Xxe2x80x21 and Exe2x80x22 mean a double bond and at the same time Xxe2x80x22 means a hydrogen atom or a group Oxe2x80x94Zxe2x80x2,
whereby Zxe2x80x2 is an aliphatic or aromatic radical with 1 to 12 C atoms, an aliphatic or aromatic acyl group with 1 to 12 C atoms or a group Exe2x80x22,
Exe2x80x21 means a group PO(ORxe2x80x29)2, a group PO(N(Rxe2x80x29)2)2, a group PO(Rxe2x80x29)2, or a group CO2Rxe2x80x29, in which
Rxe2x80x29 is a hydrogen atom or an aliphatic or aromatic radical with 1 to 12 C atoms,
Exe2x80x22 means a group PO(ORxe2x80x29)2, a group PO(N(Rxe2x80x29)2)2, a group PO(Rxe2x80x29)2, a group CO2Rxe2x80x29 or a hydrogen atom,
Qxe2x80x2 means a hydrogen atom, an aliphatic or aromatic radical with 1 to 12 C atoms or a hydroxyl group, a group xe2x80x94O(CO)Rxe2x80x210, a fluorine, chlorine, or bromine atom, an amino group or a group NHRxe2x80x210, or N(Rxe2x80x210)2, in which
Rxe2x80x210 is an aliphatic or aromatic radical with 1 to 12 C atoms.
The substances according to the invention have a considerably higher metabolic stability than the structurally related compounds of the prior art and are therefore suitable in a special way for systemic administrations.
Relative to the structurally related compounds of the prior art, some of the substances according to the invention are also characterized in that they show a stronger effect on cell differentiation, whereby the action on the calcium balance does not increase.
Surprisingly enough, it was found for some of the substances according to the invention that they specifically require the creation of new bone material without simultaneously producing an increase in the serum calcium level.
Others of the substances according to the invention, however, exhibit an antagonistic or partial agonistic profile of action, which makes possible new uses.
Determination of Biological Activity
The vitamin D activity of the substances according to the invention is determined with the aid of the calcitriol-receptor test. It is carried out using a protein extract from the intestines of juvenile pigs. Receptor-containing protein extract is incubated in a test tube with 3H-calcitriol (5xc3x9710xe2x88x9210 mol/l) in a reaction volume of 0.27 ml in the absence and in the presence of test substances for two hours at 4xc2x0 C. To separate free and receptor-bonded calcitriol, a charcoal-dextran absorption is carried out. 250 xcexcl of a charcoal-dextran suspension is fed to each test tube and incubated at 4xc2x0 C. for 20 minutes. Then, the samples are centrifuged at 10,000 g for 5 minutes at 4xc2x0 C. The supernatant is decanted and measured in a xcex2-counter after 1 hour of equilibration in Picofluor 15(trademark).
The competition curves that are obtained at various concentrations of test substance as well as of reference substance (unlabeled calcitriol) at constant concentration of the reference substance (3H-calcitriol) are placed in relation to one another, and a competition factor (KF) is determined.
It is defined as a quotient of the concentrations of the respective test substance and the reference substance, which are necessary for 50% competition:
KF=Concentration of test substance at 50% competition/Concentration of reference substance at 50% competition
To determine the acute hypercalcemic action of various calcitriol derivatives, the test that is described below is carried out:
The action of control (solution base), reference substance (1,25-dihydroxy vitamin D3=calcitriol) and test substance is tested in each case after one-time subcutaneous administration in groups of 10 healthy male rats (140-170 g). During the testing time, the rats are kept in special cages to determine the excretion of water and mineral substances. Urine is collected in two fractions (0-16 hours and 16-22 hours). An oral dose of calcium (0.1 mmol of calcium in 6.5% alpha-hydroxypropyl-cellulose, 5 ml/animal) replaces at 1600 hours the calcium intake that is lacking by food deprivation. At the end of the test, the animals are killed by decapitation and exsanguinated to determine the serum-calcium values. For the primary screen test in vivo, an individual standard dose (200 xcexcg/kg) is tested. For selected substances, the result is supported by establishing a dose-effect relation.
A hypercalcemic action is shown in serum-calcium level values that are higher than in the control.
The significance of differences between substance groups and controls and between test substance and reference substance are supported with suitable statistical processes. The result is indicated as dose ratio DR (DR=factor of test substance dose/reference substance dose for comparable actions).
The differentiation-stimulating action of calcitriol analogues is also detected quantitatively.
It is known in the literature [Mangelsdorf, D. J. et al., J. Cell. Biol. 98: 391 (1984)] that the treatment of human leukemia cells (promyelocyte cell line HL 60) in vitro with calcitriol induces the differentiation of cells to macrophages.
HL 60 cells are cultivated in tissue culture medium (RPMI 10% fetal calf serum) at 37xc2x0 C. in an atmosphere of 5% CO2 in air.
For substance testing, the cells are centrifuged off, and 2.0xc3x97105 cells/ml in phenol red-free tissue culture medium is taken up. The test substances are dissolved in ethanol and diluted with tissue culture medium without phenol red to the desired concentration. The dilution stages are mixed with the cell suspension at a ratio of 1:10, and 100 xcexcl each of this cell suspension that is mixed with substance is pipetted into an indentation of a 96-hole plate. For control, a cell suspension is mixed analogously with the solvent.
After incubation for 96 hours at 37xc2x0 C. in 5% CO2 in air, 100 xcexcl of an NBT-TPA solution (nitro blue tetrazolium (NBT), final concentration in the batch of 1 mg/ml, tetradecanoyl phorbolmyristate-13-acetate (TPA), final concentration in the batch of 2xc3x9710xe2x88x927 mol/l) is pipetted into each indentation of the 96-hole plate in the cell suspension.
By incubation for 2 hours at 37xc2x0 C. and 5% CO2 in air, NBT is reduced to insoluble formazan because of the intracellular oxygen radical release, stimulated by TPA, in the cells that are differentiated to macrophages.
To complete the reaction, the indentations of the 96-hole plate are suctioned off, and the cells are affixed to the bottom of the plate by adding methanol and dried after affixing. To dissolve the intracellular formazan crystals that are formed, 100 xcexcl of potassium hydroxide (2 mol/l) and 100 xcexcl of dimethyl sulfoxide are pipetted into each indentation and ultrasonically treated for 1 minute. The concentration of formazan is measured by spectrophotometry at 650 nm.
As a yardstick for the differentiation induction of HL 60 cells to macrophages, the concentration of formed formazan applies. The result is indicated as a dose ratio (DR=factor of test substance dose/reference substance dose for comparable semi-maximum actions).
The results of the calcitriol-receptor test and the determination of the dose ratio of the differentiation induction of HL 60 cells and the dose ratio for hypercalcemia are summarized below:
Examples of test substances:
(5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid dimethyl ester 5
(5Z, 7E, 22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid diethyl ester 9
(5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5,7,10(19),22-tetraen-24a-yl)phosphonic acid bis(1-methylethyl)ester 13
(5Z,7E,22E)-(1S,3R,24"xgr")-(1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10(19),22-tetraene-24,24a-diyl)bis[phosphonic acid diethyl ester] 29
(5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid diethyl ester 53
(5Z,7E,22E)-(1S,3R)-(1,3-Dihydroxy-26,27-dimethyl-24-oxo-9,10-secocholesta-5,7,10(19),22-tetraen-25-yl)phosphonic acid diethyl ester 57
(5Z,7E,22E)-(1S,3R,24R)-(1,3,24-Trihydroxy-9,10-secochola-5,7,10(19),22-tetraen-24-yl)phosphonic acid-bis(1-methylethyl)-ester 65b
Comparison Substance
Calcitriol
In addition to a considerable affinity to the vitamin D receptor, the compounds listed show a pronounced cell-differentiating activity.
The induction of a hypercalcemia is carried out, however, only at very much higher doses than in the case of calcitriol.
The creation of new bone material is induced even at a non-hypercalcemic dose.
By the reduced property of triggering a hypercalcemia as well as the high metabolic stability, the substances according to the invention are suitable in a special way for the production of pharmaceutical agents for the treatment of diseases that are characterized by hyperproliferation and deficient cell differentiation. Included in these are, for example, hyperproliferative diseases of the skin (psoriasis, pityriasis subia pilasis, acne, ichthyosis) and pruritus, as well as tumor diseases and precancerous stages (for example, tumors of the intestines, carcinomas of the breast, lung tumors, prostate carcinomas, leukemias, T-cell lymphomas, melanomas, Batazell Larzin, squamous carcinoma, actinic keratoses, cervix dysplasias, and metastasizing tumors of any type).
Also, for the treatment and prophylaxis of diseases that are characterized by a disequilibrium of the immune system, the substances according to the invention are suitable. These include eczemas and diseases of the atopic Formon series and inflammatory diseases (rheumatoid arthritis, respiratory tract diseases, e.g., asthma), as well as auto-immune diseases, such as, for example, multiple sclerosis, diabetes mellitus type I, myasthenia gravis, lupus erythematosus, scleroderma, bullous skin diseases (pemphigus, pemphigoid), further rejection reactions in the case of autologous, allogeneic or xenogeneic transplants, as well as AIDS. In all of these diseases, the new compounds of general formula I can be combined advantageously with other substances that have an immunosuppressive action, such as cyclosporin A, FK 506, rapamycin and anti-CD 4-antibodies.
The substances are also suitable for therapy of secondary hyperparathyroidism and renal osteodystrophia because of the property of calcitriols to drop the parathormone synthesis.
Owing to the presence of the vitamin D receptor in the insulin-producing cells of the pancreas, the substances are suitable by increasing the insulin secretion for the therapy of diabetes mellitus type II.
Further, it has been found, surprisingly enough, that by topical application of the compounds according to the invention on the skin of mice, rats and guinea pigs, an increased reddening of the skin and increase of the thickness of the epidermis can be induced. The increase in the reddening of the skin is determined based on the increase in the red value of the skin surface that can be quantified with a calorimeter. The red value is typically increased 1.5-fold after the substance (dose 0.003%) is administered three times at intervals of 24 hours. The increase in the thickness of the epidermis is quantified in the histological preparation. It is typically increased 2.5-fold. The number of proliferating epidermal cells (cells in the S-phase of the cell cycle) is determined by flow cytometry and is typically increased by a factor of 6.
These properties of the derivatives in the vitamin D series according to the invention can appear suitable for therapeutic use in the case of atrophic skin, as it occurs in natural skin aging because of increased, light exposure or medicinally-induced skin atrophy by treatment with glucocorticoids.
Moreover, wound healing can be accelerated by topical application with the new compounds.
In cell populations of the hair follicle, which contribute decisively to hair growth or to hair cycle regulation, it was possible to detect vitamin D3 receptor proteins [Stumpf, W. E. et al., Cell Tissue Res. 238, 489 (1984); Milde, P. et al., J. Invest. Dermatol. 97, 230 (1991)]. In addition, in vitro findings on isolated hair follicle keratinocytes show a proliferation-inhibiting and differentiation-stimulating influence of 1,25-(OH)2D3.
From clinical observations, it is known that the vitamin D3-resistant rickets often accompanies alopecia, which develops in early infancy. Experimental findings show that the vitamin D3 bonding site of the VDR in this disease mutates, i.e., is defective [Kristjansson, K. et al., J. Clin. Invest. 92, 12 (1993)]. Keratinocytes, which were isolated from the hair follicles of these patients, do not react in vitro to the addition of 1,25-(OH)2D3 [Arase, S. et al., J. Dermatol. Science 2, 353 (1991)].
These findings indicate a decisive role for 1,25-(OH)2D3 in the regulation of hair growth.
These analogues are therefore especially suitable for the production of pharmaceutical agents for the treatment of diseases which accompany disrupted hair growth (androgenetic alopecia, alopecia areata/totalis, chemotherapy-induced alopecia) or for supporting physiological hair growth without causing the side-effects of calcitriol (especially hypercalcemia).
Senile and postmenopausal osteoporosis is characterized by an increased bone turnover with an overall negative balance. Owing to the bone shrinkage especially of trabecular bones, fractures result to an increased extent. Owing to the stimulating action of calcitriol, both in the number and the conduct of synthesis of cells forming new bones (osteoblasts), the substances according to the invention are suitable for therapy and prophylaxis of senile and postmenopausal osteoporosis (EP 0 634 173 A1), of steroid-induced osteoporosis as well as for accelerated healing of arthroplasties without causing the side-effects of calcitriol (especially hypercalcemia). For the therapy of various forms of osteoporosis, they can be combined advantageously with estradiol or other derivatives of estrogen.
Finally, it was possible to show that calcitriol increases the synthesis of a growth substance for nerve cells (nerve growth factor) [M. S. Saporito et al. Brain Res. 633, 189 (1994)]. The compounds according to the invention are therefore also suitable for treating degenerative diseases of the peripheral and central nervous system, such as Alzheimer""s disease and amyotrophic lateral sclerosis.
In addition, it has been found that certain compounds of general formula I in HL 60 cells antagonize, surprisingly enough, the action of calcitriol (see also WO 94/07853, WO 97/00242).
Such compounds can be used for the therapy of hypercalcemias, such as, for example, in hypervitaminosis D or intoxication with calcitriol and calcitriol-like active substances, or in the case of increased extrarenal calcitriol synthesis in granulomatous diseases (sarcoidosis, tuberculosis). Also, paraneoplastic hypercalcemias (for example, in osteolytic metastases and tumors with increased synthesis of parathormone-related peptides) as well as in hypercalcemias in the case of hyperparathyroidism.
In addition, calcitriol antagonists can be used for birth control. In the reproductive tracts of female and male animals, the vitamin D receptor is expressed. It is known that the female and male fertility of vitamin-D-deficient animals is reduced. By short-term substitution of calcitriol, the reproductive output can be increased. Calcitriol antagonists are therefore able to influence female and male fertility.
Since calcitriol, under certain conditions, shows an immunosuppressive action, calcitriol receptor antagonists can also be used as immunostimulants, e.g., in the case of weak defenses against infections, AIDS.
Calcitriol is known to be able to modulate hair growth. Calcitriol antagonists can therefore be used therapeutically in the case of undesirable hair growth, e.g., in hirsutism.
Vitamin D has long been known to play a stimulating role in the formation of arteriosclerotic plaque. In such vascular lesions, a calcitriol-regulated protein, osteopontin, is found to be increased, to which a role in vascular sclerosis is attributed [R. Eisenstein et al. Arch. Path. 77, 27 (1964), L. A. Fitzpatrick et al., J. Clin. Invest. 94, 1597 (1994)]. Calcitriol antagonists are therefore suitable for therapy and prophylaxis of all types of arteriosclerosis.
Finally, calcitriol antagonists are suitable because of the property of calcitriol to increase unspecific immune reactions of monocytic cells, for therapy of inflammatory diseases, especially of a chronic nature, such as rheumatoid arthritis, Crohn""s disease, ulcerative colitis, and granulomatous diseases such as sarcoidosis and other foreign-body reactions.
For all listed therapeutic applications, it is true that the compounds according to the invention are able to achieve a therapeutic action in the above-mentioned clinical pictures without causing the side-effects of calcitriol (especially hypercalcemia).
This invention thus relates to pharmaceutical preparations that contain at least one compound according to general formula I together with a pharmaceutically compatible vehicle.
The compounds can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles or as pills, tablets or capsules, which contain solid vehicles in a way known in the art. For topical use, the compounds are advantageously formulated as creams or ointments or in a similar form of pharmaceutical agent that is suitable for topical use. Each such formulation can also contain other pharmaceutically compatible and nontoxic adjuvants, such as, e.g., stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring additives. The compounds are advantageously administered by injection, intravenous infusion of suitable sterile solutions, as an aerosol via bronchial tubes and lungs, or as oral dosage via the alimentary tract or topically in the form of creams, ointments, lotions or suitable transdermal patches, as is described in EP-A 0 387 077.
The daily dose is approximately 0.1 xcexcg/patient/day-1000 xcexcg/patient/day, preferably 1.0 xcexcg/patient/day-500 xcexcg/patient/day.